The overall objective of this integrated group of research studies is a more comprehensive understanding of the pathophysiology of unipolar and bipolar affective disorder, as well as the more recently described seasonal affective disorder. The further development of our outpatient department has enabled us to greatly expand the investigative capacities of the inpatient unit. In contrast with previous years, the average admission for a patient with depression is short, approximately three weeks. During this time patients undergo a series of neuroendocrine, neurochemical and sleep and circadian studies which will enable us to further characterize their depressions. Patients with major affective disorder undergo a trial of partial sleep deprivation which may produce immediate therapeutic effects. Patients who are not improved are then started on drug therapy as part of double-blind investigations which are continued in the outpatient department. Shorter hospital stays have enabled us to increase the number of patients studied and to expedite therapy. Our ability to identify diagnostic subgroups, predictors or response and to test specific hypotheses have all been exhausted. At the same time we have expanded our longitudinal studies of affective patients in two ways: (1) descriptive studies of rapid cycling manic depressive in entrained conditions; (2) studies of selected patients in conditions where they are isolated fromtime cues (temporal isolation). The primary treatment modalities under investigation are: (1) environmental manipulations such as partial sleep deprivation and phototherapy; (2) tricyclic antidepressants showing specificity for given neurotransmitter systems; and (3) trials of euthyroid and hypermetabolic doses of thyroxine in rapid cycling manic depressives.